Prognostic Significance of the Bone Marrow-to-Aorta Uptake Ratio on 2-Deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography/Computed Tomography in Patients with Cholangiocarcinoma.

2-Deoxy-2-[18F]fluoro-d-glucose (FDG) uptake of the reticuloendothelial system on positron emission tomography/computed tomography (PET/CT) is known to be related to systemic inflammatory response to cancer cells in patients with diverse malignancies. This retrospective study aimed to investigate whether FDG uptake by the reticuloendothelial system had a prognostic value in predicting progression-free survival (PFS) and overall survival (OS) in 138 cholangiocarcinoma patients. Quantifying FDG uptake of the aorta, bone marrow (BM), liver, and spleen from staging FDG PET/CT images, we found significant correlations between the BM-to-aorta uptake ratio (BAR), spleen-to-aorta uptake ratio, and BM-to-liver uptake ratio with tumor stage and serum inflammatory markers. In the multivariate survival analysis, BAR was an independent predictor of PFS (p = 0.016; hazard ratio, 2.308) and OS (p = 0.030; hazard ratio, 2.645). Patients with stages III-IV of the disease and a high BAR exhibited low 1-year PFS (35.8%) and OS (60.2%) rates, while those with stages I-II of the disease and low BAR showed robust rates of 90.0% and 96.7%, respectively. BAR measured on staging FDG PET/CT might be a potential imaging biomarker offering insights into the systemic inflammatory response and predicting prognosis in cholangiocarcinoma. This study highlights BAR as a promising, independent predictor with potential for personalized prognostication and treatment strategies.

Oral tranexamic acid treats papulopustular rosacea by improving the skin barrier.

BACKGROUND: Papulopustular rosacea (PPR) is a chronic inflammatory disease with a significant impact on facial aesthetics. An impaired skin barrier is an important factor in the development and exacerbation of PPR. Tranexamic acid (TXA) has immune regulatory and anti-inflammatory effects, inhibits angiogenesis and endothelial hyperplasia, and promotes skin barrier repair. AIMS: We investigated the efficacy and safety of oral TXA for PPR treatment. PATIENTS/METHODS: In total, 70 patients were randomly assigned to receive traditional therapy plus oral TXA or traditional therapy alone for 8 weeks, with a 4-week follow-up period. The subjective improvement in rosacea was assessed using the clinical erythema assessment (CEA), investigator's global assessment (IGA), patient self-assessment (PSA) score, rosacea-specific quality of life (RQoL) score, and global aesthetic improvement score (GAIS). An objective improvement in rosacea was assessed using skin hydration, trans-epidermal water loss (TEWL), clinical photography, and an eight spectrum facial imager. RESULTS: CEA/IGA/PSA, dryness, and RQoL scores were significantly lower and GAIS was higher in the TXA group than in the traditional therapy group. Furthermore, oral TXA significantly improved skin barrier function, increased skin hydration, and decreased TEWL, with no significant side effects. Notably, we observed better outcomes and a greater improvement in skin barrier function with TXA treatment in patients with dry-type rosacea than in patients with oily skin. CONCLUSIONS: The addition of oral TXA to traditional therapy can lead to rapid and effective improvements in PPR, which may be attributed to improvements in skin barrier function.

Relationship of FDG PET/CT imaging features with tumor immune microenvironment and prognosis in colorectal cancer: a retrospective study.

BACKGROUND: Imaging features of colorectal cancers on 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) have been considered to be affected by tumor characteristics and tumor immune microenvironment. However, the relationship between PET/CT imaging features and immune reactions in tumor tissue has not yet been fully evaluated. This study investigated the association of FDG PET/CT imaging features in the tumor, bone marrow, and spleen with immunohistochemical results of cancer tissue and recurrence-free survival (RFS) in patients with colorectal cancer. METHODS: A total of 119 patients with colorectal cancer who underwent FDG PET/CT for staging work-up and received curative surgical resection were retrospectively enrolled. From PET/CT images, 10 first-order imaging features of primary tumors, including intensity of FDG uptake, volumetric metabolic parameters, and metabolic heterogeneity parameters, as well as FDG uptake in the bone marrow and spleen were measured. The degrees of CD4+, CD8+, and CD163 + cell infiltration and interleukin-6 (IL-6) and matrix metalloproteinase-11 (MMP-11) expression were graded through immunohistochemical analysis of surgical specimens. The relationship between FDG PET/CT imaging features and immunohistochemical results was assessed, and prognostic significance of PET/CT imaging features in predicting RFS was evaluated. RESULTS: Correlation analysis with immunohistochemistry findings showed that the degrees of CD4 + and CD163 + cell infiltration and IL-6 and MMP-11 expression were correlated with cancer imaging features on PET/CT. Patients with enhanced inflammatory response in cancer tissue demonstrated increased FDG uptake, volumetric metabolic parameters, and metabolic heterogeneity. FDG uptake in the bone marrow and spleen was positively correlated with the degree of CD163 + cell infiltration and IL-6 expression, respectively. In multivariate survival analysis, the coefficient of variation of FDG uptake in the tumor (p = 0.019; hazard ratio, 0.484 for 0.10 increase) and spleen-to-liver uptake ratio (p = 0.020; hazard ratio, 24.901 for 1.0 increase) were significant independent predictors of RFS. CONCLUSIONS: The metabolic heterogeneity of tumors and FDG uptake in the spleen were correlated with tumor immune microenvironment and showed prognostic significance in predicting RFS in patients with colorectal cancer.

Prognostic Impact of Visceral Adipose Tissue Imaging Parameters in Patients with Cholangiocarcinoma after Surgical Resection.

Visceral adiposity is known to be related to poor prognosis in patients with cholangiocarcinoma; however, the prognostic significance of the qualitative features of adipose tissue in cholangiocarcinoma has yet to be well defined. This study investigated the prognostic impact of adipose tissue imaging parameters reflecting the quantity and qualitative characteristics of subcutaneous (SAT) and visceral (VAT) adipose tissue on recurrence-free survival (RFS) and overall survival (OS) in 94 patients undergoing resection of cholangiocarcinoma. The area, mean computed tomography (CT) attenuation, and mean 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake of SAT and VAT on positron emission tomography (PET)/CT for staging work-up were measured, and the relationship of these adipose tissue imaging parameters with clinicopathological factors and survival was assessed. TNM stage, histologic grade, lymphovascular invasion, and the size of cholangiocarcinoma showed positive correlations with adipose tissue imaging parameters. Multivariate survival analysis demonstrated that the visceral-to-subcutaneous adipose tissue area ratio (VSR) (p = 0.024; hazard ratio, 1.718) and mean FDG uptake of VAT (p = 0.033; hazard ratio, 9.781) were significant predictors for RFS, but all of the adipose tissue imaging parameters failed to show statistical significance for predicting OS. In addition to visceral adiposity, FDG uptake of VAT might be a promising prognostic parameter for predicting RFS in patients with cholangiocarcinoma.

Prediction of MET Overexpression in Lung Adenocarcinoma from Hematoxylin and Eosin Images.

Mesenchymal epithelial transition (MET) protein overexpression is a targetable event in non-small cell lung cancer and is the subject of active drug development. Challenges in identifying patients for these therapies include lack of access to validated testing, such as standardized immunohistochemistry assessment, and consumption of valuable tissue for a single gene/protein assay. Development of prescreening algorithms using routinely available digitized hematoxylin and eosin (H&E)-stained slides to predict MET overexpression could promote testing for those who will benefit most. Recent literature reports a positive correlation between MET protein overexpression and RNA expression. In this work, a large database of matched H&E slides and RNA expression data were leveraged to train a weakly supervised model to predict MET RNA overexpression directly from H&E images. This model was evaluated on an independent holdout test set of 300 overexpressed and 289 normal patients, demonstrating a receiver operating characteristic area under curve of 0.70 (95th percentile interval: 0.66 to 0.74) with stable performance characteristics across different patient clinical variables and robust to synthetic noise on the test set. These results suggest that H&E-based predictive models could be useful to prioritize patients for confirmatory testing of MET protein or MET gene expression status.

NAMPT-Driven M2 Polarization of Tumor-Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer.

Nicotinamide phosphoribosyltransferase (NAMPT) is a metabolic enzyme with key roles in inflammation. Previous studies have examined the consequences of its upregulated expression in cancer cells themselves, but studies are limited with respect to its role in the other cells within the tumor microenvironment (TME) during colorectal cancer (CRC) progression. Using single-cell RNA sequencing (scRNA-seq) data, it is founded that NAMPT is highly expressed in SPP1+ tumor-associated macrophages (TAMs), a unique subset of TAMs associated with immunosuppressive activity. A NAMPThigh gene signature in SPP1+ TAMs correlated with worse prognostic outcomes in CRC patients. The effect of Nampt deletion in the myeloid compartment of mice during CRC development is explored. NAMPT deficiency in macrophages resulted in HIF-1α destabilization, leading to reduction in M2-like TAM polarization. NAMPT deficiency caused significant decreases in the efferocytosis activity of macrophages, which enhanced STING signaling and the induction of type I IFN-response genes. Expression of these genes contributed to anti-tumoral immunity via potentiation of cytotoxic T cell activity in the TME. Overall, these findings suggest that NAMPT-initiated TAM-specific genes can be useful in predicting poor CRC patient outcomes; strategies aimed at targeting NAMPT may provide a promising therapeutic approach for building an immunostimulatory TME in CRC progression.

Cytokine and Chemokine Profiles in Acute Severe Fever with Thrombocytopenia Syndrome and Scrub Typhus in South Korea.

In East Asia, severe fever with thrombocytopenia syndrome (SFTS) and scrub typhus, which are common endemic tick- and mite-mediated diseases sharing common clinical manifestations, are becoming public health concerns. However, there are limited data on the comparative immunopathogenesis between the two diseases. We compared the cytokine profiles of SFTS and scrub typhus to further elucidate immune responses that occur during the disease courses. We prospectively enrolled 44 patients with confirmed SFTS and 49 patients with scrub typhus from July 2015 to December 2020. In addition, 10 healthy volunteers were enrolled as healthy controls. A cytometric bead array was used to analyze plasma samples for 16 cytokines. A total of 68 plasma samples, including 31 (45.6%) from patients with SFTS and 37 (54.4%) from patients with scrub typhus, were available for cytokine measurement. There were three cytokine expression patterns: increased levels in both SFTS and scrub typhus (interleukin 6 [IL-6], IL-10, interferon gamma induced protein 10 [IP-10], and granulocyte-macrophage colony-stimulating factor [GM-CSF]), highest levels in SFTS (interferon alpha [IFN-α], IFN-γ, granulocyte-CSF [G-CSF], monocyte chemotactic protein 1 [MCP-1], macrophage inflammatory protein 1α [MIP-1α], and IL-8), and distinct levels in scrub typhus (IL-12p40, tumor necrosis factor alpha [TNFα], IL-1ß, regulated on activation and normally T-cell expressed and secreted [RANTES], IL-17A, and vascular endothelial growth factor [VEGF]). Although patients with acute SFTS and scrub typhus exhibited partly shared expression patterns of cytokines related to disease severity, the different profiles of cytokines and chemokines might contribute to higher mortality in SFTS than in scrub typhus. Discrete patterns of helper T cell-related cytokines and VEGF might reflect differences in CD4 T-cell responses and vascular damage between these diseases.

Hermetia illucens Fermented with Lactobacillus plantarum KCCM12757P Alleviates Dextran Sodium Sulfate-Induced Colitis in Mice.

Inflammatory bowel disease (IBD) can severely affect humans and animals and is difficult to treat. Black soldier fly (Hermetia illucens; Hi) larvae (BSFL) are a sustainable source of protein. However, no studies exist on the antioxidant and anti-inflammatory functions of BSFL or fermented BSFL with respect to IBD. In this study, riboflavin-producing Lactobacillus plantarum KCCM12757P was isolated from a fish farm tank, and in conjunction with hot water-extracted Hi (HeHi) (termed HeHi_Lp), was used to determine optimal fermentation conditions to increase vitamin B2 concentration. This in vivo study investigated the therapeutic effects and mechanistic role of HeHi_Lp in chronic colitis-induced murine models. Histological changes, inflammatory cytokine levels, and intestinal barrier function were explored. Gut microbial communities and gene expression in the nuclear factor (NF)-κB signaling pathway were also studied. HeHi_Lp remarkably reduced the disease activity index, inflammatory cytokine (inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, interleukin (IL-6 and IL-1ß) levels, and increased body weight and colon length. HeHi_Lp administration significantly raised zonula occludens 1, occludin and claudin 1 and improved the composition of the gut microbiota and beneficial intestinal bacteria. These results suggest that HeHi_Lp can be used as a dietary supplement in pet food to alleviate colitis.

Evaluating the Necessity of Adaptive RT and the Role of Deformable Image Registration in Lung Cancer with Different Pathologic Classifications.

BACKGROUND: This study aimed to analyze differential radiotherapy (RT) responses according to the pathological type of lung cancer to see the possibility of applying adaptive radiotherapy (ART). METHODS: ART planning with resampled-computed tomography was conducted for a total of 30 patients (20 non-small-cell lung cancer patients and 10 small-cell lung cancer patients) using a deformable image registration technique to reveal gross tumor volume (GTV) changes according to the duration of RT. RESULTS: The small-cell lung cancer group demonstrated an average GTV reduction of 20.95% after the first week of initial treatment (p = 0.001), whereas the adenocarcinoma and squamous cell carcinoma groups showed an average volume reduction of 20.47% (p = 0.015) and 12.68% in the second week. The application of ART according to the timing of GTV reduction has been shown to affect changes in radiation dose irradiated to normal tissues. This suggests that ART applications may have to be different depending on pathological differences in lung cancer. CONCLUSION: Through these results, the present study proposes the possibility of personalized treatment options for individual patients by individualizing ART based on specific radiation responses by pathologic types of lung cancer.

The elderly population are more vulnerable for the management of colorectal cancer during the COVID-19 pandemic: a nationwide, population-based study.

BACKGROUND/AIMS: The impact of coronavirus disease 2019 (COVID-19) on the management of colorectal cancer (CRC) may worse in elderly population, as almost all COVID-19 deaths occurred in the elderly patients. This study aimed to evaluate the impact of COVID-19 on CRC management in the elderly population. METHODS: The numbers of patients who underwent colonoscopy, who visited hospitals or operated for CRC in 2020 and 2021 (COVID-19 era) were compared with those in 2019, according to 3 age groups (≥70 years, 50-69 years, and ≤49 years), based on the nationwide, population-based database (2019-2021) in South Korea. RESULTS: The annual volumes of colonoscopy and hospital visits for CRC in 2020 were more significantly declined in the old age group than in the young age group (both P<0.001). In addition, the annual volume of patients operated for CRC numerically more declined in old age group than in young age group. During the first surge of COVID-19 (March and April 2020), old age patients showed statistically significant declines for the monthly number of colonoscopies (-46.5% vs. -39.3%, P<0.001), hospital visits (-15.4% vs. -7.9%, P<0.001), CRC operations (-33.8% vs. -0.7%, P<0.05), and colonoscopic polypectomies (-41.8% vs. -38.0%, P<0.001) than young age patients, compared with those of same months in 2019. CONCLUSIONS: Elderly population are more vulnerable for the management of CRC during the COVID-19 pandemic. Therefore, the elderly population are more carefully cared for in the management of CRC during the next pandemic.

The Anti-Atopic Dermatitis Effects of Mentha arvensis Essential Oil Are Involved in the Inhibition of the NLRP3 Inflammasome in DNCB-Challenged Atopic Dermatitis BALB/c Mice.

The NLRP3 inflammasome is upregulated by various agents, such as nuclear factor-kappa B (NF-κB), lipopolysaccharide (LPS), and adenosine triphosphate (ATP). The NLRP3 inflammasome facilitations the maturation of interleukin (IL)-1ß, a proinflammatory cytokine that is critically involved in the pathogenesis of atopic dermatitis (AD). Although the NLRP3 inflammasome clearly exacerbates AD symptoms such as erythema and pruritus, drugs for AD patients targeting the NLRP3 inflammasome are still lacking. Based on the previous findings that Mentha arvensis essential oil (MAEO) possesses strong anti-inflammatory and anti-AD properties through its inhibition of the ERK/NF-κB signaling pathway, we postulated that MAEO might be capable of modulating the NLRP3 inflammasome in AD. The aim of this research was to investigate whether MAEO affects the inhibition of NLRP3 inflammasome activation in murine bone marrow-derived macrophages (BMDMs) stimulated with LPS + ATP in vitro and in a murine model displaying AD-like symptoms induced by 2,4-dinitrochlorobenzene (DNCB) in vivo. We found that MAEO inhibited the expression of NLRP3 and caspase-1, leading to the suppression of NLRP3 inflammasome activation and IL-1ß production in BMDMs stimulated with LPS + ATP. In addition, MAEO exhibited efficacy in ameliorating AD symptoms in a murine model induced by DNCB, as indicated by the reduction in dermatitis score, ear thickness, transepidermal water loss (TEWL), epidermal thickness, and immunoglobulin E (IgE) levels. Furthermore, MAEO attenuated the recruitment of NLRP3-expressing macrophages and NLRP3 inflammasome activation in murine dorsal skin lesions induced by DNCB. Overall, we provide evidence for the anti-AD effects of MAEO via inhibition of NLRP3 inflammasome activation.

Radio Tracking Reveals the Home Range and Activity Patterns of Nutria (Myocastor coypus) in the Macdo Wetland in South Korea.

Nutria (Myocastor coypus) are semi-aquatic rodents that were introduced in South Korea for commercial farming but significantly damaged aquatic ecosystems. Understanding nutria ecological behavior is essential for developing effective control and eradication strategies to mitigate their impacts. Thus, this study aimed to investigate the home range and activity patterns of 24 nutria (12 males and 12 females) in the Macdo wetland in South Korea from 2015-2016 through radio tracking. The average minimum convex polygon home range of the nutria was 0.29 ± 0.55 km2, with a 95% kernel density estimation (KDE) home range of 0.43 ± 0.85 km2 and a 50% KDE home range of 0.05 ± 1.1 km2. The home range of males was larger than that of females; however, the winter home range of females was as large as that of males. The home range also varied seasonally, with the smallest observed in winter. The nutria showed crepuscular and nocturnal activity patterns throughout the year, with no significant difference between sexes. The activities in spring, summer, and autumn showed no significant differences, but the activity in winter was significantly different from that in the other seasons. This study may serve as a basis for developing appropriately timed and scaled management strategies to mitigate the impacts of nutria on ecosystems. In conclusion, several environmental and biological factors contribute to the behavior of nutria in South Korea.

KMT2D links TGF-ß signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity.

Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-ß to the activin A pathway. We found that TGF-ß upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the protumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.

Effect of Menaquinone-4 on Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclast Differentiation and Ovariectomy-Induced Bone Loss.

Osteoporosis is a progressive metabolic disease characterized by decreased bone mineral density and increased fracture risk. Previous studies have shown that higher intake of vitamin K (VK) correlates with a reduced risk of osteoporosis. However, the effect of menaquinone-4 (MK-4), a specific form of VK, still remains obscure. Therefore, in this study, we investigated the effects of MK-4 on osteoclast differentiation by differentiating RAW 264.7 cells into osteoclasts with the help of receptor activator of nuclear factor-kappa B ligand (RANKL), assessed the mRNA expression of osteoclast-specific genes, and studied the effects of MK-4 in vivo in ovariectomized mice, a postmenopausal osteoporosis murine model. MK-4 inhibited osteoclast differentiation, decreased the mRNA expression of nuclear factor of activated T cells c1 (NFATc1), osteoclast-associated receptor (OSCAR), and cathepsin K (CTSK), and inhibited bone loss in ovariectomized mice. The findings strongly suggest that MK-4 is a therapeutic alternative for postmenopausal osteoporosis.

Multiple arterial-phase MRI with gadoxetic acid improves diagnosis of hepatocellular carcinoma ≤3.0 cm.

BACKGROUND AND AIMS: Multiple arterial-phase magnetic resonance imaging (MA-MRI) was introduced to overcome the limitations of gadoxetic acid-enhanced MRI, but its clinical impacts on hepatocellular carcinoma (HCC) diagnosis have not been well assessed. We investigated whether MA-MRI with gadoxetic acid could improve the diagnosis of HCC ≤3.0 cm in comparison with single arterial-phase MRI (SA-MRI). METHODS: This retrospective study included 397 patients from two tertiary institutions who underwent gadoxetic acid-enhanced MRI (243 patients with 271 lesions in cohort-1 underwent SA-MRI, and 154 patients with 166 lesions in cohort-2 underwent MA-MRI). The patients had 437 hepatic lesions ≤3.0 cm with pathologic confirmation. The arterial-phase image quality and diagnostic performance of SA-MRI and MA-MRI were analysed and compared. To minimize the effects of selection bias because of potential confounding between the two groups, propensity score-matching was additionally performed. RESULTS: MA-MRI showed a significantly higher percentage of optimal arterial-phase timing (94.2% vs. 74.5%, p < .001) and lower incidence of inadequate examinations (1.3% vs. 5.8%, p = .034) than SA-MRI. MA-MRI had a significantly higher non-rim arterial-phase hyperenhancement (APHE) detection rate (94.9% vs. 85.5%, p = .005) and sensitivity for diagnosing HCC (87.4% vs. 70.0%, p < .001) than SA-MRI, but no significant difference in specificity (92.9% vs. 93.1%, p = .966). In 123 pairs of propensity score-matched patients, MA-MRI had significantly higher sensitivity (89.1% vs. 74.5%, p = .006) than SA-MRI with equal specificity (92.3% vs. 92.3%, p > .999). CONCLUSIONS: Compared with SA-MRI, MA-MRI with gadoxetic acid can detect more non-rim APHE and significantly improve sensitivity for diagnosing HCC ≤3.0 cm, without a significant decrease in specificity.

Visualization Score of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging: The Effect on the Diagnostic Accuracy for Hepatocellular Carcinoma.

BACKGROUND: The visualization score of hepatobiliary-phase (HBP) images has been introduced as an image quality index for gadoxetic acid-enhanced MRI. It may be associated with hepatic function and could have an implication on the diagnostic accuracy for hepatocellular carcinoma (HCC). PURPOSE: To investigate the association between the visualization score of gadoxetic acid-enhanced MRI and clinical factors and to evaluate its effect on the diagnostic accuracy for HCC ≤ 3.0 cm. STUDY TYPE: Retrospective. POPULATION: A total of 493 focal lesions from 397 patients. FIELD STRENGTH/SEQUENCE: A 5-T or 3.0 -T with pre/postcontrast T1-weighted 3D gradient echo sequence, and T2-weighted fast spin-echo sequence ASSESSMENT: Child-Pugh classification and albumin-bilirubin (ALBI) score were assessed. Three readers evaluated the visualization score of each MRI examination (A, no or minimal; B, moderate; and C, severe limitations), and major features (arterial-phase hyperenhancement, washout, enhancing capsule, threshold growth) and ancillary features of each focal lesion. STATISTICAL TESTS: Univariable and multivariable logistic regression analyses were performed to determine significant clinical factors associated with a suboptimal visualization score (B or C). Generalized estimating equations were used to compare the sensitivity and specificity for diagnosing HCC between the two group (visualization score A vs. B or C). A P value < 0.05 was considered statistically significant. RESULTS: Of the 397 MRI examinations, the incidence of suboptimal visualization score was 13%. A suboptimal visualization score was significantly associated with Child-Pugh classification B or C (adjusted odds ratio [OR] = 15.2) and ALBI grade 2 or 3 (OR = 4.7). Compared with the visualization score A group, the suboptimal visualization score group showed significantly lower sensitivity (56.8% vs. 75.2%) and less frequent washout in HCC (62.2% vs. 84.0%). DATA CONCLUSION: The visualization score on gadoxetic acid-enhanced MRI can be an important image quality index and the diagnostic accuracy for HCC ≤ 3.0 cm may not be sufficient in the suboptimal visualization score group. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 3.

KDM6A Loss Recruits Tumor-Associated Neutrophils and Promotes Neutrophil Extracellular Trap Formation in Pancreatic Cancer.

Lysine (K)-specific demethylase 6A (KDM6A) is a frequently mutated tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC). However, the impact of KDM6A loss on the PDAC tumor immune microenvironment is not known. This study used a genetically engineered, pancreas-specific Kdm6a knockout (KO) PDAC mouse model and human PDAC tissue samples to demonstrate that KDM6A loss correlates with increased tumor-associated neutrophils and neutrophil extracellular traps (NET) formation, which are known to contribute to PDAC progression. Genome-wide bromouridine sequencing analysis to evaluate nascent RNA synthesis showed that the expression of many chemotactic cytokines, especially CXC motif chemokine ligand 1 (CXCL1), was upregulated in KDM6A KO PDAC cells. KDM6A-deficient PDAC cells secreted higher levels of CXCL1 protein, which in turn recruited neutrophils. Furthermore, in a syngeneic orthotopic mouse model, treatment with a CXCL1 neutralizing antibody blocked the chemotactic and NET-promoting properties of KDM6A-deficient PDAC cells and suppressed tumor growth, confirming CXCL1 as a key mediator of chemotaxis and PDAC growth driven by KDM6A loss. These findings shed light on how KDM6A regulates the tumor immune microenvironment and PDAC progression and suggests that the CXCL1-CXCR2 axis may be a candidate target in PDAC with KDM6A loss. SIGNIFICANCE: KDM6A loss in pancreatic cancer cells alters the immune microenvironment by increasing CXCL1 secretion and neutrophil recruitment, providing a rationale for targeting the CXCL1-CXCR2 signaling axis in tumors with low KDM6A.

Monitoring energy balance through clinical and serum biomarkers in patients with hematologic malignancies undergoing chemotherapy.

Despite widespread concern about energy imbalance due to tumor and chemotherapy-related side effects, little is known about detailed variations in energy input, metabolic rate, and physical activity. This study explored changes in energy balance components and serum biomarkers of patients with hematologic malignancies undergoing chemotherapy. Our prospective study included 40 patients with hematologic malignancies hospitalized for chemotherapy. We measured energy balance components, physical function, and serum biomarkers at baseline and weekly after chemotherapy for 3 weeks. Significant weight loss, representing negative energy balance, occurred at 2 (p = 0.002) and 3 weeks (p < 0.001) post-chemotherapy. Statistically reduced oral intake was observed at 3 weeks post-chemotherapy (p = 0.040), and resting energy expenditure statistically decreased according to Harris-Benedict equation, but not to Penn State University equation. Physical function according to DEMMI score decreased significantly at 3 weeks post-chemotherapy (p = 0.002). Serum biomarker analysis demonstrated significant changes in albumin, total protein, CXCL13, and GDF15, with exception of leptin. Although conventional serum biomarkers (total protein and albumin) did not reach pathological states despite their statistical differences, subgroup analysis showed CXCL13 in weight loss group and GDF15 in reduced oral intake group were significantly changed. Over half of patients (65.0%, n = 26) suffered from energy imbalance associated with weight loss and reduced oral intake during chemotherapy. Serial laboratory results suggested that novel biomarkers (CXCL13, GDF15) could be correlated with cachexic state and reduced food intake. Monitoring clinical and serum biomarkers associated with energy balance together can help identify needs for nutritional support in patients with hematologic malignancies undergoing chemotherapy.

LCK-Mediated RIPK3 Activation Controls Double-Positive Thymocyte Proliferation and Restrains Thymic Lymphoma by Regulating the PP2A-ERK Axis.

Receptor-interacting protein kinase 3 (RIPK3) is the primary regulator of necroptotic cell death. RIPK3 expression is often silenced in various cancer cells, which suggests that it may have tumor suppressor properties. However, the exact mechanism by which RIPK3 negatively regulates cancer development and progression remains unclear. This report indicates that RIPK3 acts as a potent regulator of the homeostatic proliferation of CD4+ CD8+ double-positive (DP) thymocytes. Abnormal proliferation of RIPK3-deficient DP thymocytes occurs independently of the well-known role for RIPK3 in necroptosis (upstream of MLKL activation), and is associated with an incidental thymic mass, likely thymic hyperplasia. In addition, Ripk3-null mice develop increased thymic tumor formation accompanied by reduced host survival in the context of an N-ethyl-N-nitrosourea (ENU)-induced tumor model. Moreover, RIPK3 deficiency in p53-null mice promotes thymic lymphoma development via upregulated extracellular signal-regulated kinase (ERK) signaling, which correlates with markedly reduced survival rates. Mechanistically, lymphocyte-specific protein tyrosine kinase (LCK) activates RIPK3, which in turn leads to increases in the phosphatase activity of protein phosphatase 2 (PP2A), thereby suppressing hyper-activation of ERK in DP thymocytes. Overall, these findings suggest that a RIPK3-PP2A-ERK signaling axis regulates DP thymocyte homeostasis and may provide a potential therapeutic target to improve thymic lymphoma therapies.

Impact of Baseline Muscle Mass and Myosteatosis on the Development of Early Toxicity During First-Line Chemotherapy in Patients With Initially Metastatic Pancreatic Cancer.

Objectives: Although chemotherapy is the only treatment option for metastatic pancreatic cancer (PDAC), patients frequently encounter adverse events during chemotherapy leading deterioration of patients' quality of life and treatment interruption. We evaluated the role of baseline CT-assessed body composition in predicting early toxicity during first cycle of the first-line chemotherapy in patients with metastatic PDAC. Methods: This retrospective study included 636 patients with initially metastatic PDAC who underwent first-line chemotherapy from January 2009 to December 2019. Chemotherapy regimen, baseline laboratory data, and body composition parameters acquired from baseline CT were obtained. The skeletal muscle index (SMI) was used to identify patients with a low muscle mass (SMI < 41 cm2/m2 for women, and < 43 cm2/m2 [body mass index < 25 cm/kg2] or < 53 cm2/m2 [body mass index ≥ 25 cm/kg2] for men), and myosteatosis was defined as low-attenuated muscle area divided by skeletal muscle area (LAMA/SMA index) ≥ 20%. Univariate and multivariable binary logistic regression analyses were performed using bootstrapping with 500 interactions to identify predictors of grade 3-4 toxicity and any treatment-modifying toxicity which led to a dose reduction, delayed administration, drug skip or discontinuation. Results: During the first cycle of the first-line chemotherapy, grade 3-4 toxicity and treatment-modifying toxicity occurred in 160 patients (25.2%) and in 247 patients (38.8%), respectively. The presence of both low muscle mass and myosteatosis was significantly associated with the occurrence of both grade 3-4 toxicity (odd ratio [OR], 1.73; 95% confidence interval [CI], 1.14-2.63) and treatment-modifying toxicity (OR, 1.83; 95% CI, 1.26-2.66) whereas low muscle mass alone did not. Conclusions: The presence of both low muscle mass and myosteatosis assessed on baseline CT may be used to predict early chemotherapy-related toxicity in patients with metastatic PDAC.